Understanding the cellular basis of learning and memory formation in the brain will lead to drug interventions that can ameliorate the memory loss associated with many modern diseases. Long-term potentiation (LTP) in the hippocampus, a brain structure known to be important for human memory formation, involves long-lasting increases in synaptic efficacy which are thought to form the basis of memory storage in the brain. The cellular events that initiate LTP occur in the postsynaptic neuron. In contrast, the longer lasting phases of LTP appear to involve alterations in presynaptic neurotransmitter release, leading to the requirement for a retrograde signal which travels from postsynaptic to presynaptic cells during the initiation of LTP. The main objective of this proposal is to further our understanding of how 3 different putative retrograde molecules function in synaptic transmission and plasticity in the hippocampus. One goal of this study is to characterize the mechanisms by which the recently identified neural messenger nitric oxide (NO), and 2 other diffusible signals, carbon monoxide and arachidonic acid, regulate synaptic transmission and plasticity in the hippocampus. Another aim is to determine whether LTP induction results in the activity of a putative NO target, an ADP-ribosyltransferase. Studies are proposed to characterize NO-stimulated ADP-ribosylated proteins in the hippocampus and to assess their contributions to synaptic transmission and long-term potentiation. Finally, the existence of diffusible signals in the hippocampus predicts that many synapses near the site of signal generation may be influenced. Following from this idea, studies are proposed to characterize the spreading of synaptic potentiation that has been observed between synapses into neighboring CA1 pyramidal neurons.